Causes, consequences, and therapy of tumors acidosis

Abstract

While cancer is commonly described as "a disease of the genes," it is also associated with massive metabolic reprogramming that is now accepted as a disease "Hallmark." This programming is complex and often involves metabolic cooperativity between cancer cells and their surrounding stroma. Indeed, there is emerging clinical evidence that interrupting a cancer's metabolic program can improve patients' outcomes. The most commonly observed and well-studied metabolic adaptation in cancers is the fermentation of glucose to lactic acid, even in the presence of oxygen, also known as "aerobic glycolysis" or the "Warburg Effect." Much has been written about the mechanisms of the Warburg effect, and this remains a topic of great debate. However, herein, we will focus on an important sequela of this metabolic program: the acidification of the tumor microenvironment. Rather than being an epiphenomenon, it is now appreciated that this acidosis is a key player in cancer somatic evolution and progression to malignancy. Adaptation to acidosis induces and selects for malignant behaviors, such as increased invasion and metastasis, chemoresistance, and inhibition of immune surveillance. However, the metabolic reprogramming that occurs during adaptation to acidosis also introduces therapeutic vulnerabilities. Thus, tumor acidosis is a relevant therapeutic target, and we describe herein four approaches to accomplish this: (1) neutralizing acid directly with buffers, (2) targeting metabolic vulnerabilities revealed by acidosis, (3) developing acid-activatable drugs and nanomedicines, and (4) inhibiting metabolic processes responsible for generating acids in the first place.

Keywords: Anti-acidic therapy; Cancer; Exosomes; Microenvironment acidity.

Figure 1.. Mechanisms to export H⁺ and maintain intracellular pH.

Extracellular pH is sensed with acid receptors, either G-protein coupled receptors OGR1, TDAG8, GPR4, or acid sensing ion channels, TRPV1 or ASICs. Because metabolism results in acid production, acid equivalents are removed from the cytoplasm by a multitude of mechanisms, each with their own regulation and behavior. These include (from left) monocarboxylate transporters to remove lactic acid, N-hydrogen exchange, vaculoar H-ATPase, and Na-driven uptake of bicarbonate, which is then removed from the cell as CO2, and re-hydrated with exofacial carbonic anhydrases

Figure 2:. Acid phenotypic heterogeneity and metabolic cooperativity in tumors

(counterclockwise from lower left). The diffusion distance of O2 in tissues is ca. 0.2 mm, and cells that are further from this from a blood vessel are hypoxic, and rely on fermentative metabolism. Fermentative cells (orange) metabolize glucose and produce lactic acid, which is removed by MCT1 or MCT4. The lactic is taken up by an adjacent oxidative cell and oxidized to CO2. In tumors (in this case a colorectal cancer), the expression of MCT4, often associated with fermentation, can be expressed in both cancer cells and adjacent stroma, emphasizing the tumor-stromal metabolic cooperativity.

Figure 3:. Metabolic adaptations to growth in an acidic environment.

After prolonged growth in acidic conditions, cells are metabolically reprogrammed to increase reliance on respiration, fueled by fatty acid oxidation, coupled to a profound decrease in glycolysis. These are coupled to chronic autophagy, storage of lipids in adiposomes, increased lysosomogenesis and redistribution of lysosomes to be adjacent to the plasma membrane. All of these are necessary adaptations and reveal metabolic vulnerabilities.

Figure 4:. Consequences of extracellular acidosis.

Following cellular adaptations described above, there are a number of systemic consequences to acidosis as well. These include (counterclockwise from top) remodeling of the extracellular matrix, allowing local invasion, leading to increased metastasis to other organs as well as bone, where the tumor generated acidity can be a potent effector of bone pain via ASICs (figure1). Local invasion is associated also with expression of acid generating cells at the invading edge. Acidic tumors are resistant to radiation and chemotherapy and, in some systems, can induce angiogenesis and lymphangiogenesis, which paradoxically often leads to poorer perfusion. Finally, acid is a potent inhibitor of effector T cell function, inhibiting immune surveillance.